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Cornea 19(2): 163–169, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia

Confocal of a Patient with Irregular After LASIK Reoperations and Relaxation Incisions

Tuuli U. Linna, M.D., Minna H. Vesaluoma, M.D., Ph.D., W. Matthew Petroll, Ph.D., Ahti H.A. Tarkkanen, M.D., Ph.D., and Timo M.T. Tervo, M.D., Ph.D.

Purpose. -assisted in situ (LASIK) is After its original introduction in 1990 (1), laser as- widely used for correcting refractive errors. If the predicted sisted in situ keratomileusis (LASIK) gained increasing refractive result is not achieved after the first operation, a re- operation can be performed by ablating more stromal tissue popularity worldwide in correction of refractive errors. after reopening the flap. The goal of this study was to analyze, In LASIK an ∼140- to 160-␮m-thick hinged flap con- by using in vivo , the morphologic sisting of the epithelium, Bowman’s layer, and anterior changes associated with repeated LASIKs. Methods. Clinical stroma is created by an automated microkeratome. The examination, computed , and real-time in stromal bed is subsequently subjected to vivo confocal microscopy were performed on both of a 50-year-old patient with induced irregular astigmatism leading photoablation, and the flap is then repositioned without to decreased best-corrected vision in the left after LASIK. sutures on the photoablated stromal surface. If the initial The left had been operated on 5 times (LASIK with two refractive correction is inadequate, a reoperation can eas- reoperations followed by two relaxing incisions), and the right ily be performed by opening the flap and reablating more cornea twice (LASIK with one reoperation). Results. Micro- folds at the level of the Bowman’s layer and highly reflective tissue with excimer laser. Reoperations are often called particles at the flap interface were observed in both . adjustments, enhancements, or refinements, but they still The subbasal nerve plexus was severed in the left eye. In ad- present further manipulation of the corneal tissue. dition, we identified epithelial material in the flap margin and The final visual and refractive outcomes after refrac- inside one of the two relaxing incisions placed inferotempo- tive surgery largely depend on the wound-healing reac- rally. Conclusion. Repeated LASIKs may stretch the flap and result in microfolding at the Bowman’s layer. This and depo- tions. Healing responses after other refractive proce- sition of particles in the flap interface may increase with the dures, such as (RK) and photorefrac- number of reoperations, challenging the healing response. Mi- tive keratectomy (PRK), have been subjected to intensive crofolding and occurrence of foreign material in the interface research (for reviews, see 2–5), but only a few studies may add to the irregular astigmatism and poor visual outcome after LASIK. Clinical in vivo confocal microscopy offers new have dealt with the healing process after LASIK (6–11). possibilities for the assessment of ultrastructural changes after One of the main advantages of LASIK is that it leaves the corneal . central optical zone clinically almost devoid of scar tis- Key Words: Confocal microscopy—Enhancement— sue. The Bowman’s layer is severed only in the flap Interface—LASIK—Microfolds—Refractive surgery— margins, which leaves the central epithelium, Bowman’s Reoperation. layer, and anterior keratocytes untouched. The hinged- flap technique results in preservation of the nerve chan- nels in the flap, although the axons are cut at the wound Submitted February 4, 1999. Revision received May 25, 1999. Ac- cepted May 28, 1999. margin (8,12). Part of the subbasal nerve plexus as well From Helsinki University Eye Hospital, Helsinki, Finland (T.U.L., as some stromal nerves are preserved in the hinge of the M.H.V., A.H.A.T., T.M.T.T.); and Department of , flap (13). University of Texas, Southwestern Medical Center at Dallas, Texas, U.S.A. (W.M.P.). Experimental animal models and immunohistochem- The authors have no financial or proprietary interest on any materials istry have been the conventional methods in studying or methods described in the article. wound-healing reactions after refractive surgery. How- Address correspondence and reprint requests to Dr. T. Linna, De- partment of Ophthalmology, University of Helsinki, PL 220, 00029 ever, the real-time in vivo confocal microscopy (CM), a Huch, Finland. E-mail: [email protected] new method, is now available for the assessment of

163 164 T.U. LINNA ET AL. wound-healing reactions (6,10,14–18). We present in In the beginning of August 1997, an astigmatic kera- vivo CM findings of a patient whose left cornea had been totomy of the left eye (one incision, inferotemporally operated on 5 times (LASIK with two reoperations and 30°) was performed, but the refraction did not change. relaxing incisions twice) and right cornea twice (LASIK The computed corneal topography showed a central is- with one reoperation). This study not only revealed heal- land. Biomicroscopy revealed some foreign material in ing problems in both corneas, but also confirmed that the flap interface. According to the patient record, a sec- CM is a powerful method for the assessment of corneal ond astigmatic keratotomy was performed in October micromorphology after refractive surgery. 1997, but it only increased the astigmatism. In November 1997, the refraction of the left eye was −2.5 cyl + 1.0 ax 170, and a myopic LASIK (third LASIK) was per- MATERIALS AND METHODS formed. One week afterward, the refraction was −1.5 cyl Patient History −3.25 ax 30. The patient complained about difficulties in reading and night halos, and described that “the left eye In January 1998, a 50-year-old healthy man was re- was useless.” After all these treatments, BCVA of the ferred to the Helsinki University Eye Hospital for evalu- right eye was at the preoperative level (20/25), but ation of irregular astigmatism and decreased best- BCVA of the left eye was worse (20/40–20/30). The corrected (BCVA) of his left eye after mul- patient consulted another ophthalmic , who re- tiple keratorefractive operations. The history started in ferred him to the University Eye Hospital of Helsinki for May 1997, when the patient’s left eye was operated on further examination. for by using the LASIK technique (by a surgeon not affiliated with the authors; an automated microkera- Clinical Examination tome, Corneal Shaper system, Chiron Vision, Irvine, CA, U.S.A.; Aesculap Meditech MEL60 excimer laser). The Clinical examination including biomicroscopy, refrac- preoperative cycloplegic refractions were −8.5 cyl +0.75 tion, corneal photographs, and corneal computed topo- ax 170 in the right and −8.75 cyl +1.0 ax 70 in the left graphic maps (Eye Sys System 2000, software version eye. Preoperatively the BCVA was 20/25 for both eyes. 3.2; Eye Sys Technologies, Inc., Houston, TX, U.S.A.) Pachymetry showed a central corneal thickness of 572 was performed in Helsinki University Eye Hospital in mm for the right and 575 mm for the left eye, and intra- January 1998. ocular pressures (IOPs) were 19 and 22 mm Hg, respec- tively. Owing to the patient’s presbyopic age, the at- In Vivo Confocal Microscopy tempted final refraction was −1.0 diopter (D). The left eye underwent LASIK first. According to the original A tandem scanning CM (TSCM; model 165A; Tan- patient record, the flap did not adhere well to the under- dem Scanning Corporation, Reston, VA, U.S.A.) lying stroma, and a therapeutic was fit for 1 equipped with a 24×/0.6 NA immersion objective lens day. During the first postoperative days, the patient an- was used in this study. The illumination of this CM was ticipated that something had gone wrong. One week after supplied by a 100-W mercury lamp, and it was designed LASIK, the refraction of the left eye was reported to be for full-thickness examination of the cornea. The internal +2.0 cyl +2.25 ax 0. Biomicroscopy revealed no pathol- lenses of the objective were moved with a motorized ogy, and the flap appeared to be well positioned. The focusing device (18011 Encoder Mike TM Controller; overcorrection was supposed to have resulted from a Oriel, Stratford, CT, USA) interfaced to a Pentium com- failure of the excimer laser. A hyperopic LASIK correc- puter system (Gateway 2000, Inc., N. Sioux City, SD, tion of +3.0 cyl +1.25 ax 0 was performed 1 week after U.S.A.), to vary the focal plane relative to the objective the first myopic LASIK. The flap could be opened easily. tip. Real-time images were captured by using a low-light At the postoperative control on the following day, the level video (VE-1000 Sit System; Dage-MTI refraction was −2.25 D, and the uncorrected visual acuity Inc., Michigan City, IN, U.S.A.), and the images were (UCVA) was 20/40. The central cornea was clear, but recorded on an S-VHS videotape (Fuji) by using a vid- some edema was observed in the flap margins. eocassette recorder (Panasonic AG-7355). With this ob- A myopic LASIK of the right eye was performed in jective and camera, the field-of-view was ∼450 × 360 June 1997 without problems, but 1 week after the opera- ␮m, and the optical slice thickness (z-axis resolution) tion, both overcorrection and induced astigmatism were was 9 ␮m. For the assessment of the thickness of the observed again (refraction, +1.25 cyl +1.5 ax 160). A whole cornea, the epithelium, and the keratomileusis hyperopic LASIK of +1.0 cyl +1.0 ax 170 was performed flap, a confocal microscopy through-focusing (CMTF) in July 1997. On the following day, the slit-lamp exami- was performed as described earlier (18,19). Before the nation appeared normal, and a week later, the refraction examination, one drop of topical anesthetic (benoxinate was −0.25, but the UCVA was only 20/30. hydrochloride, Oftan Obucain; Santen, Tampere, Fin-

Cornea, Vol. 19, No. 2, 2000 CONFOCAL MICROSCOPY AFTER REPEATED LASIKs 165

land) and one drop of 2.5% hydroxymethylcellulose gel × 80°. The topography of the left eye showed astigma- (Goniosol; IOLAB Pharmaceuticals, Claremont, CA, tism Յ4.7 D with bent axis (superiorly 95°, and inferi- U.S.A.) were applied on the cornea to be examined. The orly, 315°). Simulated K-values were 40.5 D × 15° and patient used the contralateral eye to fixate on a bright 30.3 D × 105°. Potential visual acuities (PVA) were 20/ object to minimize eye movements during examination. 25–20/30 for the right eye and 20/30–20/40 for the left The objective lens of the was adjusted to eye, which corresponds to the acquired BCVAs. give a tangential view of the central part of each cornea to confirm the proper alignment, after which CMTF Confocal Microscopy scans were performed. Additional en face or slightly ob- lique sections of interesting-looking anatomic details The total thickness of the central cornea was 512 ␮m also were obtained. in the right and 465 ␮m in the left eye. The epithelial thicknesses were 61 and 65 ␮m, respectively. The flap RESULTS interface could be identified in the depth of ∼121 ␮min ␮ Clinical Examination the right and 147 m in the left eye. Both central corneas showed normal surface epithelial cells with highly re- UCVA of the right eye was 20/32, and 20/63 for the flective nuclei and clear cellular borders (Fig. 2A). The left eye. The refractions were −0.25 cyl −1.0 ax 80 and basal epithelial cells were regular in shape, showing only ±0 cyl −2.5 ax 100, giving BCVAs of 20/20 and 20/30, the bright cellular borders (Fig. 2B). Abnormal micro- respectively. With a presbyopic add of +1.75 D, the pa- folds appeared under the basal epithelial cell layer in tient was satisfied with his near vision. There was a both corneas in an area corresponding to the Bowman’s significant difference in both the lens power and BCVA layer (Fig. 2B–F). Folding appeared to be more promi- of the left eye compared with what was reported a few nent in the left cornea, exhibiting more irregular astig- weeks earlier in the charts of the operating surgeon. The matism. Right behind these microfolds, normal- biomicroscopy revealed that both flaps were well posi- appearing anterior keratocytes were identified in both tioned. Some foreign material, however, could be ob- eyes (Fig. 2C, E, and F). Subbasal nerves were not iden- served in the interface of the left eye. A moderate circu- tified in the left central cornea. The right central cornea, lar haze was observed at the flap margins in both cor- however, showed a few subbasal nerve fibers (Fig. 2E). neas. The temporal flap margin of the left cornea showed A thin, somewhat strangely branching stromal nerve was local regions of increased fibrosis probably due to ma- observed in the right cornea (Fig. 2G). Thick stromal nipulation during repeated opening of the flap (Fig. 1). nerves could be identified deeper in the normal- Both flaps appeared to contain fine folds in the central appearing stroma behind the flap in both corneas (Fig. area. In addition, bright material was perceived in one of 2H). the relaxing incisions of the left cornea (Fig. 1). The CMTF scan showed an intensity peak correspond- ing to the flap interface (Fig. 3), which could easily be Corneal Topography identified in both corneas by using CM because of the The computed corneal topography of the right eye highly reflective particles of variable size and shape. showed simulated K-values of 40.4 D × 170° and 38.6 D There appeared to be considerably more particles in the left flap interface (compare Fig. 4A and B). The wound- healing reaction, or haze formation (i.e., keratocyte ac- tivation and extracellular matrix production) was almost negligible at the right interface. Only a few keratocytes were surrounded by bright reflections corresponding to a minimal haze (Fig. 4C). The cellular response was slightly more prominent in the left eye. The stroma pos- terior to the flap interface (Fig. 4D) and endothelium of both corneas appeared normal (Fig. 4E). The relaxing incision of the left peripheral cornea had a low-intensity reflection inside the stromal wound. This area was interpreted to represent epithelial ingrowth into the wound. This presumed continuous epithelial plug was found to reflect light similar to the basal epithelial cells. Basal epithelial cell borders, however, were not FIG. 1. The photograph of the left cornea shows the tem- poral flap margin with focal areas of fibrosis. The astig- perceived. In the middle of the epithelial plug, there were matic keratotomy incision (arrow) shows some bright ac- numerous bright, round accumulations (Fig. 4F), which cumulations. were regarded as epithelial cell debris. Deposition of

Cornea, Vol. 19, No. 2, 2000 166 T.U. LINNA ET AL.

FIG. 2. A: Confocal image of normal sur- face epithelial cells of the left cornea show- ing bright nuclei and clear cellular borders (scale bar, 100 µm). B: Normal basal epi- thelial cells (arrow) of the left cornea pre- senting with bright cellular borders. A mi- crofold at the level of the Bowman’s layer also is shown. C: A microfold at the level of the Bowman’s membrane of the left cor- nea. Normal anterior keratocyte nuclei (ar- row) are also shown. D: Microfolds of the left cornea. E: A subbasal nerve leash (ar- row) of the right cornea. A microfold and anterior keratocyte nuclei are also shown. F: Normal-looking anterior keratocytes and a deep microfold of the left cornea. G: A thin stromal nerve (arrow) of the right cornea with somewhat abnormal structure. H: A thick stromal nerve (arrow) posterior to the flap interface of the right cornea.

extracellular matrix typical of tissue fibrosis appeared as ered otherwise normal, although the keratocyte processes increased reflectivity on both sides of the incision in the appeared to be vaguely perceivable, perhaps due to ac- adjacent stroma. tivation or altered hydration in the region. The wound at the periphery of the flap of the right cornea also was investigated. Epithelial ingrowth was DISCUSSION found at the wound margin (Fig. 4G). The anterior stroma on both sides of the peripheral interface showed LASIK offers quite a few advantages over PRK, such scar-tissue deposition (Fig. 4G). Despite haze, the flap as increased patient comfort with less-painful, faster vi- interface was also easily identified at the wound margin sual recovery, and less regression and haze formation owing to the bright particles (Fig. 4H). These particles (20,21). Although most of the patients are satisfied with were far more numerous in the interface of the flap pe- the final outcome after LASIK, the surgery also has po- riphery near the entering point of the microkeratome than tentially serious complications. Most of them are flap in the central region (compare Fig. 4A and H). The bright problems related to the creation of the flap with the mi- particles were of variable size. The stroma under the crokeratome (partial flap, free flap, lost flap, thin flap, lamellar interface of the wound periphery was consid- uneven flap, loose flap, damage to the anterior segment)

Cornea, Vol. 19, No. 2, 2000 CONFOCAL MICROSCOPY AFTER REPEATED LASIKs 167

mechanical stretching and adhesion problems, and even- tually result in a folded flap and persistence of irregular astigmatism. Furthermore, the contour of the stromal bed will be altered after laser photoablation, which may in- herently impair the compatibility between the flap and the stromal bed (26). We observed more prominent mi- crofolds at the level of the Bowman’s layer in the eye, which had undergone a greater amount of surgical ma- nipulation. Slowik et al. (10) also reported marked folds in the interface area and in the lenticle of a patient who had been retreated, and suggested that they had been induced by the redetachment and bending of the flap. Pérez-Santonja et al. (23) described fine wrinkles (stria- tions) resembling fingerprint lines in the flap after LASIK with biomicroscopy. Baumgartner and Binder (27) also reported folds and “microfractures” in Bow- man’s layer in human keratomileusis lenticules by using light microscopy, and associated them with bending of the flap. On the other hand, in electron microscopy of rabbit corneas subjected to a single LASIK, the area of basal lamina of the epithelium has been reported to show normal structure (7). However, the rabbit cornea does not contain a Bowman’s layer comparable to that of humans, and the mechanical stability of this layer of the anterior stroma may be incomparable between humans and rab- bits. Amm et al. (7) showed that in rabbits, it was difficult to detect the flap interface because of only a few traces of repair. In our study, localization of the interface was FIG. 3. A: A CMTF intensity profile of a normal cornea easy, because of the highly reflective interface particles (540 µm) showing intensity peaks corresponding to differ- hallmarked with some keratocyte reaction. Similar find- ent corneal structures (compare with Fig. 4B). B: A CMTF profile of the left cornea (465 µm) of the LASIK patient ings were earlier reported by Nagel et al. (6) and Slowik showing additional intensity peaks corresponding to mi- et al. (10). The interface of the left cornea with a total of crofolding and flap interface. three LASIKs showed more of these reflective particles than the right cornea with less manipulation. The origin of the foreign material in the flap interface is unclear, but or the postoperative period (epithelial ingrowth, retained includes different possibilities such as metal particles debris in the flap interface, malposition of the flap, folds from the microkeratome blade, cotton particles from the in the flap, or flap melting; 6,10,22–24). Failure of the swabs, powder from the gloves, inflammatory cells, or laser or decentration of laser also is possible. epithelial remnants. The number of interface particles After reopening of the LASIK flap, some of the possible after surgery seems to decrease with time (M. Ve- complications can be controlled. Striae, or folds, can be saluoma, unpublished results), which suggests that at smoothed, foreign material or epithelial ingrowth can be least some of the interface particles represent inflamma- removed from the flap interface, or overcorrection or tory cells. Inflammatory cells are capable of phagocytos- regression can be treated with enhancement surgery ing foreign material present in the interface, and kerato- (25,26). The flap can be lifted with blunt dissection with- cytes have been shown to have a vigorous endocytotic out a new microkeratome cut at least up to 6 months. The activity in vivo (28). We perceived more particles in the time point after surgery is crucial for the impact the interface near the flap margins than in the central area; reopening of the flap has on the healing cornea and its the blade of the microkeratome could have carried this nerves. Multiple reopenings, although unusual and not material from the tear film or epithelial surface, shedding desired, may be necessary to obtain clinically and func- it all the way through the cut, but left most of it near the tionally acceptable results. entry of the wound. Furthermore, the keratocyte reaction With the aid of CM, microfolds at the level of the appeared to correlate with the amount of interface par- Bowman’s layer could readily be identified. Repeated ticles. The keratocyte response with scar-tissue deposi- lifting and repositioning of the flap may cause further tion was slightly more prominent in the left cornea that

Cornea, Vol. 19, No. 2, 2000 168 T.U. LINNA ET AL.

FIG. 4. A: A confocal image of the interface of the right central cornea showing a few reflective particles (arrow). Scale bar, 100 µm. B: The interface of the left central cor- nea with more bright particles (compare with Fig. 5A). C: Increased reflectivity of the ex- tracellular matrix (arrow) around some kera- tocytes adjacent to the interface of the left cornea. D: The normal-appearing stroma of the left cornea posterior to the interface showing keratocyte nuclei. E: The endothe- lium of the left cornea showing normal struc- ture. The nuclei of the endothelial cells can be perceived. F: The relaxing incision of the left cornea showing an epithelial plug (the area of low reflectivity) and containing pre- sumed accumulations of epithelial cell de- bris (arrow). G: The wound margin (arrow) of the right cornea showing an epithelial plug. The stroma at the interface showed scar-tissue deposition seen as increased re- flectivity of the extracellular matrix. H: De- spite the fibrosis, the interface of the flap periphery of the right cornea was perceived easily owing to the reflective particles.

had undergone multiple manipulations. If some of the lial ingrowth after LASIK may predispose the cornea to interface particles represented seeded epithelial cells, a flap melt or necrosis (23). Thus if significant epithelial local epithelial–stromal interaction (29,30) could have ingrowth is recognized, it is recommended to lift the flap been possible within the interface. This could well stand and debride this epithelium (23,25). In the astigmatic for the subtle keratocyte reaction observed; the epithelial keratotomy wound of the left peripheral cornea, we ob- material could have been in contact with the keratocytes served an epithelial plug with round “pea-like” accumu- within the interface, and initiated the cytokine cascade, lations of presumable epithelial cell debris inside it. We resulting in keratocyte apoptosis, subsequent prolifera- also demonstrated minimal epithelial ingrowth in the tion of activated keratocytes, and production of new ex- margin of the flap. tracellular matrix (29,30). The level of keratocyte apop- LASIK cuts the superficial stromal nerves in the flap tosis after LASIK is variable, and it can be recognized in margin, and the nerves of the stromal bed are subse- deeper central corneal keratocytes anterior and posterior quently exposed to excimer laser photoablation. On the to the lamellar cut (31). other hand, the hinge of the flap spares some of the Epithelial plugs in the keratotomy wounds (32) and epithelial and anterior stromal nerves, and the flap itself epithelial ingrowth into the LASIK interface (25) are preserves the original Schwann cell pathways (8,12). In known complications of refractive surgery. The epithe- rabbit corneas subjected to LASIK, the regenerating

Cornea, Vol. 19, No. 2, 2000 CONFOCAL MICROSCOPY AFTER REPEATED LASIKs 169 nerve fibers have been shown to emerge from the cut TMT. Corneal wound healing after laser in situ keratomileusis. J stromal nerves. These fibers finally penetrate the basal Refract Surg 1998;14:602–9. 12. Latvala T, Linna T, Tervo T. Corneal nerve recovery after pho- lamina of the epithelium and contribute to the formation torefractive keratectomy and laser in situ keratomileusis. Int Oph- of the new subbasal nerve plexus and intraepithelial thalmol Clin 1996:36:21–7. nerve endings (13). In our study, the central cornea of the 13. Linna TU, Pe´rez-Santonja JJ, Tervo KM, Sakla HF, Alio´ JL, Tervo TMT. Recovery of corneal nerve morphology following laser in right eye after two LASIKs showed a few parallel sub- situ keratomileusis. Exp Eye Res 1998;66:755–63. basal nerve fibers, but the left cornea after more manipu- 14. Cavanagh HD, Petroll WM, Alizadeh H, He Y-G, McCulley JP, lations had no subbasal nerves at the optical axis. The Jester JV. Clinical and diagnostic use of in vivo confocal micros- copy in patients with corneal disease. Ophthalmology 1993;100: blunt dissection of the flap may induce more neural dam- 1444–54. age and reverse all possible neural regeneration that took 15. Essepian JP, Rajipal RK, Azar DT, et al. The use of confocal place after the preceding operations. microscopy in evaluating corneal wound healing after excimer laser keratectomy. Scanning 1993;16:300–4. The reoperations after LASIK are easy to perform. 16. Corbett MC, Prydal JI, Verma S, Oliver KM, Pande M, Marshall Consequently, many recognize that enhance- J. An in vivo investigation of the structures responsible for corneal ments are justified for simple finetuning of the refractive haze after photorefractive keratectomy and their effect on visual result. Our study with in vivo CM suggests—although function. Ophthalmology 1996;103:1366–80. 17. Linna T, Tervo T. Real-time confocal microscopic observations on based on only two corneas of one patient—that repeated human corneal nerves and wound healing after excimer laser pho- LASIKs may further compromise corneal healing and torefractive keratectomy. Curr Eye Res 1997;16:640–9. increase neural damage as well as induce postoperative 18. Møller-Pedersen T, Vogel M, Li HF, Petroll WM, Cavanagh D, Jester JV. Quantification of stromal thinning, epithelial thickness, irregular astigmatism. and corneal haze after photorefractive keratectomy using in vivo confocal microscopy. Ophthalmology 1997;104:532–5. Acknowledgment: Our deepest gratitude is due to Dr. H.D. 19. Li HF, Petroll WM, Møller-Pedersen T, Maurer JK, Cavanagh HD, Cavanagh (Southwestern Medical School at Dallas, Texas, Jester JV. Epithelial corneal thickness measurements by in vivo U.S.A.), who generously contributed to getting the Tandem confocal microcopy through focusing (CMTF). 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